Vascular Consequences of Insulin Resistance and Obesity

胰岛素抵抗和肥胖对血管的影响

• 批准号: 7851079
• 负责人: Joseph A. Vita
• 金额: $ 235.15万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7851079
• 关键词: Vascular; Consequences; Insulin; Resistance; Obesity

Patients with obesity-related phenomena such as insulin resistance, the metabolic syndrome, and Type 2 diabetes mellitus, have a markedly increased risk for atherothrombosis. Investigators now recognize these conditions as representing a major threat to public health and that our current understanding and management strategies of these disorders are inadequate. Studies suggest that excess caloric intake and physical inactivity lead to a neuro-humoral imbalance that promotes obesity and insulin resistance in association with systemic inflammation and dyslipidemia. In the vascular wall, systemic factors and local insulin resistance combine to alter cellular energetics and mitochondrial function, activate innate immunity, and impair the bioavailability of endothelium-derived nitric oxide. We propose to establish a Specialized Center of Clinically-Oriented Research (SCCOR) at Boston University School of Medicine that will take a multi-disciplinary approach to define mechanisms of vascular injury in this setting. We will test the overall hypothesis that obesity and insulin resistance induce inflammation and ectopic lipid deposition in vasculature that impairs vascular function and promotes atherothrombosis. Project 1 (Dr. Vita) will test the hypothesis that inter-related effects of reduced activity of AMP-dependent protein kinase, increased production of mitochondrial-derived reactive oxygen species, and activation of innate immunity contribute to vascular dysfunction in human subjects with early insulin resistance. Project 2 (Dr. Ramachandran) will test the hypothesis that circulating adipokines and neuroendocrine and gut-derived hormones impair vascular function and will prospectively predict risk for developing obesity, hypertension, dyslipidemia, and the metabolic syndrome in the Framingham Heart Study. Project 3 (Dr. Gokce) will test the hypothesis that adipose tissue serves as a primary source of inflammatory cytokines that impair vascular function in obese patients and will examine the impact of specific weight loss strategies on vascular function and inflammation in adipose tissue. Project 4 (Dr. Freedman) will test the hypothesis that innate immunity contributes to atherothrombosis and the acute response to vascular injury by examining toll-like receptor (TLR)-mediated signaling mechanisms in leukocytes and platelets from human subjects and mouse models of obesity. Project 5 (Dr. Hamilton) will use novel magnetic resonance imaging and spectroscopy techniques to test the hypothesis that ectopic lipid deposition is a marker of vascular dysfunction and accelerated atherosclerosis in obesity and the metabolic syndrome. This project takes advantage of the unique expertise of the investigators and research resources at the Boston University Medical Campus, including strong statistical support, outstanding programs of research in basic vascular biology, novel imaging resources, clinical programs for the management of obesity, and the Framingham Heart Study. This work will improve our understanding of vascular injury in insulin resistance and obesity and may identify new approaches for patient management.

患有胰岛素抵抗、代谢综合征和 2 型糖尿病等肥胖相关现象的患者，动脉粥样硬化血栓形成的风险显着增加。研究人员现在认识到这些疾病对公共健康构成了重大威胁，并且我们目前对这些疾病的理解和管理策略还不够。研究表明，热量摄入过多和缺乏身体活动会导致神经体液失衡，从而促进肥胖和胰岛素抵抗，并与全身炎症和血脂异常相关。在血管壁中，全身因素和局部胰岛素抵抗结合起来改变细胞能量学和线粒体功能，激活先天免疫，并损害内皮源性一氧化氮的生物利用度。我们建议在波士顿大学医学院建立一个临床导向研究专业中心（SCCOR），该中心将采用多学科方法来定义这种情况下的血管损伤机制。我们将检验总体假设，即肥胖和胰岛素抵抗会引起脉管系统中的炎症和异位脂质沉积，从而损害血管功能并促进动脉粥样硬化血栓形成。项目 1（Vita 博士）将测试以下假设：AMP 依赖性蛋白激酶活性降低、线粒体衍生活性氧生成增加以及先天免疫激活等相互关联的影响会导致早期胰岛素抵抗人类受试者的血管功能障碍。项目 2（Ramachandran 博士）将测试循环脂肪因子、神经内分泌和肠道源性激素损害血管功能的假设，并将前瞻性预测弗雷明汉心脏研究中发生肥胖、高血压、血脂异常和代谢综合征的风险。项目 3（Gokce 博士）将检验脂肪组织是损害肥胖患者血管功能的炎症细胞因子主要来源的假设，并将研究特定减肥策略对脂肪组织血管功能和炎症的影响。项目 4（Freedman 博士）将通过检查人类受试者和肥胖小鼠模型的白细胞和血小板中 Toll 样受体 (TLR) 介导的信号传导机制，检验先天免疫导致动脉粥样硬化血栓形成和对血管损伤的急性反应的假设。项目 5（汉密尔顿博士）将使用新型磁共振成像和光谱技术来检验以下假设：异位脂质沉积是肥胖和代谢综合征中血管功能障碍和加速动脉粥样硬化的标志。 该项目利用了波士顿大学医学校区研究人员的独特专业知识和研究资源，包括强大的统计支持、基础血管生物学的杰出研究项目、新颖的成像资源、肥胖管理的临床项目以及弗雷明汉心脏研究。这项工作将提高我们对胰岛素抵抗和肥胖引起的血管损伤的理解，并可能确定患者管理的新方法。

项目成果

Spatio-temporal texture (SpTeT) for distinguishing vulnerable from stable atherosclerotic plaque on dynamic contrast enhancement (DCE) MRI in a rabbit model.

• DOI: 10.1118/1.4867861
• 发表时间: 2014-04
• 期刊: Medical physics
• 影响因子: 3.8
• 作者: T. Wan;A. Madabhushi;A. Phinikaridou;J. Hamilton;N. Hua;Tuan Pham;Jovanna Danagoulian;Ross Kleiman;A. Buckler

The role of inflammation in regulating platelet production and function: Toll-like receptors in platelets and megakaryocytes.

• DOI: 10.1016/j.thromres.2009.11.004
• 发表时间: 2010-03
• 期刊: Thrombosis research
• 影响因子: 7.5
• 作者: Beaulieu LM;Freedman JE
• 通讯作者: Freedman JE

Images in cardiovascular medicine. Healing of an asymptomatic carotid plaque ulceration.

心血管医学中的图像。无症状的颈动脉斑块溃疡的愈合。

• DOI: 10.1161/circulationaha.108.764779
• 发表时间: 2008-09-02
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Qiao Y;Farber A;Semaan E;Hamilton JA
• 通讯作者: Hamilton JA

Detection of thrombus size and protein content by ex vivo magnetization transfer and diffusion weighted MRI.

通过体内磁化转移和扩散加权MRI检测血栓大小和蛋白质含量。

• DOI: 10.1186/1532-429x-14-45
• 发表时间: 2012-06-25
• 期刊: Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance
• 作者: Phinikaridou A;Qiao Y;Giordano N;Hamilton JA
• 通讯作者: Hamilton JA

Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3-kinase.

• DOI: 10.1161/circresaha.108.185785
• 发表时间: 2009-02-13
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Blair P;Rex S;Vitseva O;Beaulieu L;Tanriverdi K;Chakrabarti S;Hayashi C;Genco CA;Iafrati M;Freedman JE
• 通讯作者: Freedman JE